In a trial stopped for futility, the addition of extracranial-intracranial bypass surgery improved brain perfusion but did not reduce the two-year rate of ipsilateral ischemic stroke (P=0.78), according to William Powers, MD, of the University of North Carolina at Chapel Hill, and colleagues.

There were no differences between the groups on any of the secondary endpoints either, the researchers reported in the Nov. 9 issue of the Journal of the American Medical Association.

The trial -- the Carotid Occlusion Surgery Study (COSS) -- "joins the list of stroke trials in which a successful outcome as measured by an important biologic marker of brain perfusion -- improved oxygen extraction ratio after the bypass procedure -- was not reflected in improved clinical outcome at two years," according to Joseph Broderick, MD, of the University of Cincinnati, and Philip Meyers, MD, of Columbia University in New York City.

They noted in an accompanying editorial that the event rate in the control group was much lower than expected, "possibly reflecting improvements in medical prevention of stroke during the conduct of the trial."

Patients with symptomatic atherosclerotic internal carotid artery occlusion have a high risk for stroke when they are treated medically. The two-year rate of ipsilateral ischemic stroke on medical therapy is 10% to 15%. Those with hemodynamic cerebral ischemia carry an even higher risk.

To assess the potential benefit of adding extracranial-intracranial bypass surgery to medical therapy in these high-risk patients, Powers and colleagues randomized 195 patients to surgery plus medical therapy or medical therapy alone at 49 clinical centers and 18 positron emission tomography (PET) centers in the U.S. and Canada.

The trial was stopped early after an interim analysis revealed that it was unlikely to show a significant between-group difference on the primary endpoint -- all stroke and death through 30 days from randomization or surgery, and all ipsilateral ischemic stroke within two years of randomization.

Although the addition of surgery improved oxygen extraction fraction, the two-year rate of the primary endpoint was similar in the surgery group (21%) and the control group (22.7%). All of the events were ipsilateral ischemic strokes.

At 30 days, the rate of ipsilateral stroke was 14.4% in the surgery group and 2% in the control group, a significant absolute difference of 12.4% (95% CI 4.9% to 19.9%).

There also were no between-group differences on secondary endpoints, despite patent grafts among patients who underwent surgery, at rates of 98% at 30 days and 96% at the last follow-up visit.

The researchers noted that even though the rate of stroke in the control group was lower than expected, it was similar to more recent studies of patients with asymptomatic carotid artery stenosis who received medical therapy.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS).

Powers and five of his co-authors reported receiving salary and other support from U.S. Public Health Service (PHS) grants that funded this research. Power's co-authors reported relationships with Merck, Medtronic, and W.L. Gore and Associates, a medical device company that manufactures aneurysm grafts and vascular stents.

Broderick is the principal investigator of the NINDS-funded IMS III trial, which is mentioned in the paper by Powers and colleagues, and the principal investigator of the NINDS-funded University of California SPOTRIAS Center. Broderick also reported having received consulting fees from Genentech. Consulting fees and honoraria for Broderick are placed in an educational/research stroke fund within the Department of Neurology. Meyers is the external interventional safety monitor for the IMS III trial.

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